Hepatitis B virus transgenic mice: insights into the virus and the disease
- PMID: 7557887
- DOI: 10.1016/0270-9139(95)90645-2
Hepatitis B virus transgenic mice: insights into the virus and the disease
Abstract
It should be apparent from the foregoing that the transgenic mouse model system has contributed substantially to our understanding of many aspects of HBV biology, immunobiology, and pathogenesis in the past several years. We have learned that HBV can replicate within the mouse hepatocyte, as well as other mouse cell types, suggesting that there are probably no strong tissue or species-specific constraints to viral replication once the viral genome enters the cell. However, the failure thus far to detect viral cccDNA in the hepatocyte nucleus in several independently derived transgenic lineages suggests that other, currently undefined, constraints on host range and tissue specificity may also be operative. Thanks to the transgenic mouse model, we now understand the pathophysiological basis for HBsAg filament formation and "ground glass" cell production, and we have learned that at least this viral gene product can be toxic for the hepatocyte, first by compromising its ability to survive the hepatocytopathic effects of lipopolysaccharide and gamma interferon, and eventually by causing it to die in the absence of any obvious exogenous stimulus. In recent studies, it has been shown that preformed nucleocapsid particles do not cross the nuclear membrane, in either direction, at least in the mouse hepatocyte. If this is confirmed, it will have two important implications: first, that nucleocapsid disassembly must occur in the cytoplasm before the nascent viral genome can enter the nucleus; second, that the intranuclear nucleocapsid particles are empty, and therefore serve no currently defined purpose in the viral life cycle. This should stimulate new interest in the analysis of the function of these particles that are a prominent feature of mammalian hepadnavirus infection. The transgenic mouse model has also established definitively that HBV-induced liver disease has an immunologic basis, and that the class I restricted CTL response plays a central role in this process. Additionally, the mouse studies have taught us that when the CTL recognize their target antigen on the hepatocyte they cause them to undergo apoptosis, forming the acidophilic Councilman bodies that are characteristic of viral hepatitis. Further, we have learned that although the CTL initiate the liver disease, they actually contribute more to disease severity indirectly by recruiting antigen nonspecific effector cells into the liver than by directly killing the hepatocytes themselves; and that by releasing gamma interferon when they recognize antigen, the CTL can destroy enough of the liver to cause fulminant hepatitis in mice whose hepatocytes overproduce the large envelope protein and are hypersensitive to the cytopathic effects of this cytokine.(ABSTRACT TRUNCATED AT 400 WORDS)
Similar articles
-
Hepatitis B virus transgenic mice: models of viral immunobiology and pathogenesis.Curr Top Microbiol Immunol. 1996;206:149-73. doi: 10.1007/978-3-642-85208-4_9. Curr Top Microbiol Immunol. 1996. PMID: 8608715 Review.
-
HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection.J Immunol. 1993 May 15;150(10):4659-71. J Immunol. 1993. PMID: 7683326
-
Hepatitis B virus immunopathogenesis.Annu Rev Immunol. 1995;13:29-60. doi: 10.1146/annurev.iy.13.040195.000333. Annu Rev Immunol. 1995. PMID: 7612225 Review.
-
Overcoming T cell tolerance to the hepatitis B virus surface antigen in hepatitis B virus-transgenic mice.J Immunol. 2001 Jan 15;166(2):1389-97. doi: 10.4049/jimmunol.166.2.1389. J Immunol. 2001. PMID: 11145724
-
Mechanisms of class I restricted immunopathology. A transgenic mouse model of fulminant hepatitis.J Exp Med. 1993 Nov 1;178(5):1541-54. doi: 10.1084/jem.178.5.1541. J Exp Med. 1993. PMID: 8228807 Free PMC article.
Cited by
-
Apoptosis-related proteins, BCL-2, BAX, FAS, FAS-L and PCNA in liver biopsies of patients with chronic hepatitis B virus infection.Pathol Oncol Res. 2000;6(2):130-5. doi: 10.1007/BF03032363. Pathol Oncol Res. 2000. PMID: 10936789
-
Hepatitis B virus core protein sensitizes hepatocytes to tumor necrosis factor-induced apoptosis by suppression of the phosphorylation of mitogen-activated protein kinase kinase 7.J Virol. 2015 Feb;89(4):2041-51. doi: 10.1128/JVI.03106-14. Epub 2014 Nov 26. J Virol. 2015. PMID: 25428880 Free PMC article.
-
An HBV-tolerant immunocompetent model that effectively simulates chronic hepatitis B virus infection in mice.Exp Anim. 2016 Nov 1;65(4):373-382. doi: 10.1538/expanim.16-0013. Epub 2016 Jun 6. Exp Anim. 2016. PMID: 27264142 Free PMC article.
-
Identification and characterization of peptides that interact with hepatitis B virus via the putative receptor binding site.J Virol. 2007 Apr;81(8):4244-54. doi: 10.1128/JVI.01270-06. Epub 2006 Dec 27. J Virol. 2007. PMID: 17192308 Free PMC article.
-
[Hepatitis B virus and pathogenesis].Soz Praventivmed. 1998;43 Suppl 1:S5-9, S79-83. doi: 10.1007/BF02042164. Soz Praventivmed. 1998. PMID: 9833255 Review. French, German.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous